The role of cystatin C as a proteasome inhibitor in multiple myeloma

Carfilzomib is the second proteasome inhibitor approved for relapsed multiple myeloma. Since its approval in 2012, carfilzomib has been an active and versatile drug, based on its efficacy as a single agent; superiority as a doublet with dexamethasone compared with bortezomib and dexamethasone; and as a partner in diverse three drug combinations such as with lenalidomide or daratumumab. While it has an established place in relapsed disease, clinicians should be aware of its cardiovascular and renal adverse event profile, which is manageable, in order to optimize outcomes. This review will provide a perspective on the current and future role of carfilzomib in relapsed/refractory multiple myeloma.

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Renal Thrombotic Microangiopathy Associated with the Use of Bortezomib in a Patient with Multiple Myeloma

Case Reports in Hematology ◽

10.1155/2016/6020691 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Jan Van Keer ◽

Michel Delforge ◽

Daan Dierickx ◽

Kathelijne Peerlinck ◽

Evelyne Lerut ◽

...

Keyword(s):

Multiple Myeloma ◽

Thrombotic Microangiopathy ◽

Proteasome Inhibitor ◽

First Generation ◽

Causal Role ◽

Proven Case

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated.

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The role of cystatin C in multiple myeloma

International Journal of Laboratory Hematology ◽

10.1111/ijlh.13695 ◽

2021 ◽

Author(s):

Jie Zhang ◽

Yijing Jiang ◽

Dan Guo ◽

Hai yan Liu ◽

Lemin Hong ◽

...

Keyword(s):

Multiple Myeloma ◽

Cystatin C

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The role of nuclear factor-[kappa ]B in the biology and treatment of multiple myeloma

Seminars in Oncology ◽

10.1053/sonc.2001.29542 ◽

2001 ◽

Vol 28 (6) ◽

pp. 626-633 ◽

Cited By ~ 3

Author(s):

James R. Berenson ◽

Hongjin M. Ma ◽

Robert Vescio

Keyword(s):

Multiple Myeloma ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Nuclear Factor Kappa

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Faculty Opinions recommendation of Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718106808.793484850 ◽

2013 ◽

Author(s):

Wee Joo Chng

Keyword(s):

Multiple Myeloma ◽

B Cells ◽

Proteasome Inhibitor ◽

Negative Tumor ◽

Inhibitor Resistance

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CD38 as an immunomodulator in cancer

Future Oncology ◽

10.2217/fon-2020-0401 ◽

2020 ◽

Vol 16 (34) ◽

pp. 2853-2861

Author(s):

Yanli Li ◽

Rui Yang ◽

Limo Chen ◽

Sufang Wu

Keyword(s):

Multiple Myeloma ◽

Cell Activation ◽

Human Tissues ◽

Transmembrane Glycoprotein ◽

Cell Activation Marker ◽

Research Findings ◽

A Cell ◽

And Function ◽

Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

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The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

Pharmaceuticals ◽

10.3390/ph13120451 ◽

2020 ◽

Vol 13 (12) ◽

pp. 451

Author(s):

Elena Zamagni ◽

Paola Tacchetti ◽

Paola Deias ◽

Francesca Patriarca

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Immune System ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Cellular Targets ◽

Recent Introduction

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

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Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽

10.3390/cells10061490 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1490

Author(s):

Osama M. Elzamzamy ◽

Brandon E. Johnson ◽

Wei-Chih Chen ◽

Gangqing Hu ◽

Reinhold Penner ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Transient Receptor Potential ◽

Cyclic Peptide ◽

Calcium Influx ◽

Acquired Resistance ◽

Treatment Strategies ◽

Prognostic Indicators ◽

Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

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Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

Cell Death and Disease ◽

10.1038/s41419-021-03701-z ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Xuxing Shen ◽

Chao Wu ◽

Meng Lei ◽

Qing Yan ◽

Haoyang Zhang ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Serum Enzyme ◽

Herg Channels ◽

Anti Tumor Activity ◽

Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

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DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13030504 ◽

2021 ◽

Vol 13 (3) ◽

pp. 504

Author(s):

Takayuki Saitoh ◽

Tsukasa Oda

Keyword(s):

Multiple Myeloma ◽

Dna Damage ◽

Dna Repair ◽

Tumor Microenvironment ◽

Dna Damage Response ◽

Genetic Instability ◽

Dna Repair Mechanisms ◽

Damage Response ◽

Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

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